R9.5: Methods To Overcome Tumour Hypoxia

The presence of hypoxic cells leads to treatment failures, and therefore methods to overcome this problem have been sought in many different areas. Methods typically involve increasing oxygen supply to the tumour, killing anoxic cells through different methods, or exploiting reoxygenation by delivering radiation treatment over a longer time period.

## Fractionation

Fractionation of radiation treatment allows for reoxygenation to take place between individual fractions. This leads to a reduction in the population of hypoxic cells with every treatment, and increased cell kill over what would be expected if hypoxic cells remained hypoxic. Therefore fractionation, which is commonly used for other reasons (reduction in late toxicity of normal tissues) also has significant benefit in tumour control.

Hypoxic cell radiosensitisers typically function by mimicking the role oxygen plays in fixing indirect radiation damage to DNA. The typical compound used is misonidazole (a relative of metronidazole), which if delivered in high enough concentrations to anoxic cells almost restores the cell survival curve seen in oxic conditions.
The alteration of dose required to give a similar biological effect is given by the sensitiser enhancement ratio (SER).

(1)
\begin{align} \text{SER}=\frac{\text{Dose Without Sensitiser}}{\text{Dose With Sensitiser}} \text{ for same biological effect} \end{align}

## Hypoxic Cell Cytotoxics

Instead of sensitising hypoxic cells to radiation, they can be targeted selectively by cytotoxic agents. The three drugs of this class are the quinones (eg. mitomycin-C), nitroimidazoles (eg. RSU-1069) and N-oxides (tirapazamine).
Mitomycin C was the prototype drug, and functions by causing an increased number of DNA crosslinks in hypoxic cells. It has a low discrimination between hypoxic and oxic cells and studies have shown no evidence of clinical benefit.
RSU-1069 is a nitroimidazole, similar to misonidazole, with an added aziridine ring that causes cytotoxicity in hypoxic cells. It functions as both a hypoxic cell sensitiser and cytotoxic. Side effects include blindness, as the retina is also hypoxic.
Tirapazamine is from a class of organic nitroxides, and undergoes reduction in hypoxic cells to form a toxic product. It also sensitises hypoxic cells to radiation. Initial clinical studies showed an improvement in survival but this has not carried over to phase III trials. Future directions may include selecting patients with evidence of hypoxia on PET scanning.

## Hyperbaric Oxygen

Hyperbaric oxygen therapy (HBO therapy) was first in the 1960’s to increase the oxygen pressure in tumours. Despite some differences in trial design, evidence exists that in some tumour sites (eg. head and neck) hyperbaric oxygen improves outcomes. Smaller studies failed to show significant benefit and hyperbaric oxygen therapy was abandoned in favour of cell sensitisers or cytotoxics. Patient comfort was of concern but needs to be balanced by potential pitfalls of uncontrolled disease or chemotherapy.

## Hyperthermia

Hypoxia may be reversed for up to 24 hours by heating of the tumour (up to 41.5oC). Hypoxic cells are also more sensitive to damage from heating, as the heat tends to remain in the tissue. However, achieving homogenous heat distribution through a tumour, without damaging neighbouring tissue, is a difficult task and makes hyperthermia unwieldy.